Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice

iScience

Jean Lee¹  Alexander Chervonsky¹  Mansour Mohamadzadeh²  Timothy Garrett³  Georges Abboud³  Seung-Chul Choi³  Longhuan Ma³  Josephine Brown³  Nathalie Kanda³  Laurence Morel³  Leilani Zeumer-Spataro³  Joy Cagmat³  Andras Perl⁴  Tamas Faludi⁴  Weidan Peng⁵  Laura Mandik-Nayak⁵ 

[1] Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA;Department of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA;Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA;Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, College of Medicine, Syracuse, NY 13210, USA;Lankenau Institute for Medical Research, Wynnewood, PA, USA;

关键词: Biological sciences;    Human metabolism;    Immunology;    Cell biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: A skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs in lupus-susceptible mice, and how tryptophan metabolites exacerbate T cell activation. Metabolomic analyses demonstrated that tryptophan is differentially catabolized in lupus mice compared to controls and that the microbiota played a role in this skewing. There was no evidence for differential expression of tryptophan catabolic enzymes in lupus mice, further supporting a major contribution of the microbiota to skewing. However, isolated lupus T cells processed tryptophan differently, suggesting a contribution of T cell intrinsic factors. Functionally, tryptophan and its microbial product tryptamine increased T cell metabolism and mTOR activation, while kynurenine promoted interferon gamma production, all of which have been associated with lupus. These results showed that a combination of microbial and T cell intrinsic factors promotes the production of tryptophan metabolites that enhance inflammatory phenotypes in lupus T cells.

【 授权许可】

Unknown